Antitumor and immunotherapeutic effects of activated invasive T lymphoma cells that display short-term interleukin lot expression

Expression of cytokines in malignant cells represents a novel approach for therapeutic treatment of tumors. Previously, we demonstrated the immunostim ulatory effectiveness of interleukin 1 alpha (IL-1 alpha) gene transfer in experimental fibrosarcoma tumors. Here, we report the antitumor and immunot herapeutic effects of short-term expression of IL-1 alpha by malignant T ly mphoma cells. Activation in culture of T lymphoma cells with lipopolysaccha ride-stimulated macrophages induces the expression of IL-1 alpha. The short -term expression of IL-1 alpha persists in the malignant T cells for a few days (similar to 3-6 days) after termination of the lit vitro activation pr ocedure and, thus, has the potential to stimulate antitumor immune response s in vivo. As an experimental tumor model, we used the RO1 invasive T lymph oma cell line. Upon i.v. inoculation, these cells invade the vertebral colu mn and compress the spinal cord, resulting in hind leg paralysis and death of the mice. Activated RO1 cells, induced to express IL-1 alpha in a short- term manner, manifested reduced tumorigenicity: similar to 75% of the mice injected with activated RO1 cells remained tumor free. IL-1 was shown to be essential for the eradication of activated T lymphoma cells because inject ion of activated RO1 cells together with IL-1-specific inhibitors, i.e., th e IL-1 receptor antagonist or the M 20 IL-1 inhibitor, reversed reduced tum origenicity patterns and led to progressive tumor growth and death of the m ice. Furthermore, activated RO1 cells could serve as a treatment by interve ning in the growth of violent RO1 cells after tumor take, Thus, when activa ted RO1 cells were injected 6 or 9 days after the inoculation of violent ce lls, mortality was significantly reduced. IL-1 alpha, in its unique membran e-associated form, in addition to its cytosolic and secreted forms, may rep resent a focused adjuvant for potentiating antitumor immune responses at lo w levels of expression, below those that are toxic to the host, Further ass essment of the immunotherapeutic potential of short-term expression of IL-1 alpha in activated tumor cells may allow its improved application in the t reatment of malignancies.